CN117838375A - 支架组件和制备支架组件的方法 - Google Patents
支架组件和制备支架组件的方法 Download PDFInfo
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- CN117838375A CN117838375A CN202311555614.1A CN202311555614A CN117838375A CN 117838375 A CN117838375 A CN 117838375A CN 202311555614 A CN202311555614 A CN 202311555614A CN 117838375 A CN117838375 A CN 117838375A
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- Prior art keywords
- stent
- carrier
- agent
- hydrogel
- stent assembly
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Abstract
本发明的各实施方式涉及支架组件,其包括:支架;可膨胀涂层,其设置在所述支架的外表面的至少一部分上;非必要性地,载体,其分散在可膨胀涂层中和/或设置在支架的外表面的至少一部分上;以及活性剂,该活性剂包含在可膨胀涂层或载体,如果载体存在的话,的至少其中一个内。本发明还提供了支架组件作为输尿管支架的用途,以及制备支架组件的方法。
Description
分案申请声明
本申请是2016年03月15日提交的国际申请号为PCT/SG2016/050119的PCT国际申请,于2017年11月20日进入中国国家阶段的、发明名称为“支架组件和制备支架组件的方法”、申请号为201680029258.1的中国发明专利申请的分案申请。
技术领域
本发明各实施方式一般涉及支架,更具体地涉及具有药物洗脱能力的输尿管支架。
背景技术
具有药物洗脱能力的支架可以解决与冠状动脉或外周血管阻塞或输尿管狭窄有关的问题。通常,药物被包含在覆盖支架的聚合物涂层中,并且在支架被置入待治疗对象之后,该药物可从该聚合物涂层中释放出来。然而,含药物的涂层易于脱层,特别是在支架扩张期间。在这种情况下,药物不能被输送到期望的位置或达到期望的量。因此,对于这种含有药物的涂层而言,在储存期间,特别是利用气囊使支架扩张后,能够保持其机械完整性非常重要。
在这方面,已经在输尿管道中测试了几种类型的药物洗脱支架。输尿管支架已经被用在输尿管狭窄、阻塞和损伤的患者中创建从肾脏到膀胱的排尿途径,或者用在各种手术过程中保护输尿管的完整性以及其它用途。许多临床状况可能会导致尿流中断,包括例如由于狭窄、肿瘤生长或结石引起的输尿管的内源性阻塞,由外源性肿瘤生长引起的输尿管压迫,体外冲击波碎石术(ESWL)和输尿管镜检查或腔内肾盂切开术之后的输尿管中的石头碎片压迫。因此,支架可用于治疗或预防会使从相应肾脏至膀胱的尿流中断的输尿管阻塞,该输尿管阻塞会导致尿回流到肾脏,从而威胁肾脏功能。
此外,输尿管狭窄是一个重要的泌尿系统问题,可能潜在地导致高发病率和肾脏功能丧失。输尿管狭窄可能由多种原因引起,包括石通、内窥镜泌尿系统手术、放射治疗、开腹手术或腹腔镜手术以及穿透性创伤。治疗包括在输尿管狭窄处形成全层内窥镜切口,有意引起内腔的受控穿孔和扩张,随后在6周内于留置输尿管支架上愈合。切口后6周取出支架。根据原始狭窄的长度和严重程度,可能发生复发,需要重复用内窥镜切口进行治疗,然而其成功率会下降。重复的内窥镜治疗的失败导致需要进行患病段的开放手术修复,或者甚至在肾亏损显著后需要去除同侧肾,这些都并不罕见。因此输尿管狭窄的发病并非无关紧要。
为了减少支架相关的疼痛,在一项涉及276例患者的随机研究中探索了装载Ketorolac(NSAID)的支架。展现了治疗效益的趋势。特别是将该支架制造为将药物纳入支架材料中(Boston Scientific LexingtonTM支架)。
在其他情况下,研究了在猪模型的输尿管中使用含有紫杉醇的药物洗脱支架(DES)来预防狭窄。在这种情况下,使用网状支架来减少尿路上皮响应于支架本身的增生反应。然而,在泌尿科中使用网状支架尚未得到广泛接受,主要是因为难以在不再进一步损伤尿路上皮的情况下去除网状物。因此,网状支架的使用可能更适合于需要更多永久性输尿管支架置入术的情况,例如恶性输尿管梗阻。测试了留置最长达3个月的负载了抗微生物剂(三氯生)的支架,以减少支架相关感染。虽然治疗组受到的症状性感染更少,但在尿液和支架培养方面的临床益处仍尚未得到证实。
鉴于上述情况,需要一种改进的支架来克服或至少减轻一个或多个上述问题。
发明内容
在第一方面,提供支架组件。支架组件包括
a)支架;
b)可膨胀涂层,其设置在支架的外表面的至少一部分上;
c)非必要性地,载体,其分散在可膨胀涂层中和/或设置在支架的外表面的至少一部分上;以及
d)活性剂,其包含在可膨胀涂层或载体(如果有)的至少其中一个内。
在第二方面,提供了根据第一方面的支架组件作为输尿管支架的用途。
在第三方面,提供制备支架组件的方法。所述方法包括:
a)提供支架,
b)将可膨胀材料设置在支架上;非必要性地,包括将载体分散在可膨胀材料中和/或将载体设置在支架的外表面的至少一部分上;并将活性剂并入可膨胀材料或载体,如果载体存在的话,中的至少其中一个内,以在支架的外表面的至少一部分上形成可膨胀涂层。
附图说明
为了更好地理解本发明,下面将结合以下非限制性实施例和附图对本发明进行详细说明,其中:
图1展示了根据一实施例的具有近端部分(21),中央部分(22)和远端部分(23)的输尿管支架(20)。该输尿管支架(20)上开设有小孔(27)。图中还示出了配置为将近端部分(21)保持在膀胱中的近端保持结构(25)和配置为将远端部分(23)保持在肾脏的肾盂中的远端保持结构(26)。
图2展示了定位在人体内的图1所示的输尿管支架(20)。图中展示了用于将近端部分保持在膀胱(11)中的近端保持结构(25)、用于与人类患者的输尿管(12)适配的中央部分、以及用于保持在肾脏(14)的肾盂(13)中并防止支架移位的远端保持结构(26)。
图3(A)为定位于人体输尿管中的、图1和图2所示的输尿管支架的中央部分(22)的侧视图;其中A1为沿着A1-A1线剖切的图3(A)所示支架的横截面图;A2为沿着A2-A2线剖切的图3(A)所示支架的横截面图。图3(B)展示了根据一个实施例的、具有处于未膨胀状态的可膨胀涂层(30)的、图1和图2所示的输尿管支架的中央部分(22)。其中,B1为沿着B1-B1线剖切的图3(B)所示的支架的横截面图;B2为沿着B2-B2线剖切的图3(B)所示的支架的横截面图。图3(C)展示了根据一个具体实施例的、具有处于膨胀状态的可膨胀涂层(30)且与输尿管壁(12)接触的、图1和图2所示的输尿管支架的中央部分(22)。其中,C1为沿着C1-C1线剖切的图3(C)所示的支架的横截面图;C2为沿着C2-C2线剖切的图3(C)所示的支架的横截面图。
图4(A)是根据一种实施方式的支架(20)的局部视图,该支架具有单个可膨胀层(30)和泌尿有益剂(31)。图4(B)是根据本发明公开的一个实施方式的支架(20)的局部视图,其具有单个可膨胀层(30),该层包括负载了泌尿有益剂(31)的纳米载体(33)形式的药物输送平台。图4(C)是本文公开的支架(20)的局部视图,其具有多层涂层结构,该多层涂层结构包括顶部可膨胀层(30),以及位于所述可膨胀层(30)和支架(20)之间的层(32)形式的、负载有泌尿有益剂(31)药物输送平台。图4(D)为根据一种实施方式的支架(20)的局部视图,该支架具有多层涂层结构,该多层涂层结构包括顶部可膨胀层(30),以及位于所述可膨胀层(30)和支架(20)之间的层(32)形式的第一药物输送平台。层(32)包括负载泌尿有益剂(31)的纳米载体(33)形式的第二药物递送平台。
图5展示了根据一个实施例的双层涂层支架在37℃、在水中和缓冲溶液中(pH=6.0,pH=7.4和pH=8.5)的累积丝裂霉素-C(MMC)(2.5%剂量)药物释放曲线。
图6展示了根据另一实施例的双层涂层支架在37℃、在水中和缓冲溶液中(pH=6.0,pH=7.4和pH=8.5)的累积丝裂霉素-C(MMC)(5%剂量)药物释放曲线。
图7展示了根据一实施例的双层涂层支架在37℃、在水中和缓冲溶液中(pH=6.0,pH=7.4和pH=8.5)的累积丝裂霉素-C(MMC)(7.5%剂量)药物释放曲线。
图8展示了根据一实施例的可膨胀涂层输尿管支架的扫描电子显微镜(SEM)图像。图中比例尺表示500μm。
图9为根据一实施例的双层涂层输尿管支架。如图所示,支架包括与支架接触的药物负载底层和与药物负载底层接触的水凝胶顶层。药物可以是抗增殖药、抗癌药、抗菌药、或具有两种或更多的上述性质的多功能药物。聚合物可以在留置时间内有效地和安全地提供药物的持续输送。水凝胶可用于使药物转移到尿路上皮组织中的最大化定位以克服药物渗透的高不透性。
图10(A)至(D)为展示所制备的工作原型的照片。图10(A)和图10(B)展示了涂有2cm聚合物/药物和2cm水凝胶的输尿管支架的2.5cm截面,而图10(C)和图10(D)显示了涂有双层涂层的完整支架。图10(A)和图10(C)展示了膨胀前的涂层,而图10(B)和10(D)展示了膨胀后的涂层。这证明了制造所述涂层支架的技术可行性。
图11(A)至(C)为SEM图像,其展示了涂覆有负载着药物(MMC)的聚合物、但不含水凝胶聚乙二醇(乙二醇)二丙烯酸酯(PEGDA的支架,其中各图中MMC的含量为:(A)2.5%MMC;(B)5%MMC;和(C)7.5%MMC。图11(D)为涂有含5%MMC(药物)的聚合物和水凝胶PEGDA的支架的SEM图像。图中使用的支架是聚氨酯(PU)支架。图中所示表面形态平滑,无任何药物聚集。
图12(A)和(B)是表示对于5%PEGDA,7.5%PEGDA和10%PEGDA,(A)涂层部分直径(mm)与时间的曲线图和(B)PEGDA的厚度(mm)对时间的变化。支架的水凝胶涂层能够在接触和吸收水时膨胀。该图展示了在支架浸入水中的静态条件下,涂层在30分钟至1小时内最多能够膨胀至相当于输尿管直径的4.5mm至5mm。下表1表示结果。
表1
图13(A)和(B)为展示(A)相对细胞数与MMC浓度(μg/mL)的关系和(B)剂量-反应曲线的图。
图14(A)至(D)为具有不同涂层厚度的聚合物涂层支架和可膨胀双层涂层支架在pH为7.4的磷酸盐缓冲液(PBS)中的MMC的体外释放研究图。释放曲线由聚合物厚度(20μm,120μm,240μm和46μm)和药物负载(2.5%MMC,5.0%MMC和7.5%MMC)控制,以达到广泛的药物量,在大约90-200μg累积MMC释放28天以上;日剂量高于0.01μg/mL的最低药物浓度,抑制成纤维细胞增殖。
图15(A)和(B)为(A)水凝胶涂层对PBS(pH=7.4)中累积MMC释放(μg)的影响;和(B)水凝胶涂层影响(放大1天)。当在体外使用时,水凝胶涂层对药物释放曲线没有显著影响。在最初的几个小时,用水凝胶涂层涂覆的样品释放的药物量略高一些。这可能是由于具有水凝胶的样品的药物释放较早发生。在干燥步骤中,药物层仍然暴露于水性水凝胶层,并开始将药物释放到水凝胶中。然后,储存在水凝胶中的药物开始与水凝胶中的水接触,此时,水凝胶开始膨胀。然而,在体内,可膨胀的水凝胶能够作为桥梁来增强或输送药物到输尿管组织。当水凝胶存在时,最初释放的药物量稍高。
图16为展示MMC洗脱输尿管支架对如下样品的成纤维细胞抑制作用的图,其中,样品1:无药物,无支架;样品2:0.5ug/mL MMC;样品3:支架/PLC/PEGDA;样品4:支架/PLC/MMC(5%);样品5:支架/PLC/MMC(5%)/PEGDA。
图17(A)和(B)为本文公开的支架的实施例的锥形端的照片。对涂层施加锥形端设计以解决和/或缓解与涂层膨胀后支架的可移除性有关的问题。
图18(A)至(E)的照片展示了:(A)涂层支架可以通过成人膀胱镜(22F,40cm)插入猪输尿管;(B)涂层支架从肾脏切口置于输尿管内;(C)从近端(肾脏部位)注射造影剂,X-射线图像显示支架在输尿管道的正确位置。在凝胶膨胀之前,造影剂能够穿过支架的内腔和侧面(支架表面和尿路上皮组织之间的间隙);以及(D)将涂层支架置于输尿管35分钟以允许膨胀。注射造影剂,观察到造影剂能穿过支架的内腔而不是侧面,这表明本发明的水凝胶在体内能够在35分钟内膨胀并与尿路上皮组织接触;(E)容易且成功地移除支架。最终膨胀后直径测得4mm,与尿道直径相当。这表明支架可以容易地从输尿管插入和移除,并且支架上的涂层部分能够在猪输尿管中膨胀。
具体实施方式
在第一方面中,提供一种支架组件。本文公开的支架组件能够抑制输尿管成纤维细胞增殖,以防止狭窄复发。通过在支架的外表面的至少一部分上引入可膨胀涂层,当与介质接触时,可膨胀涂层最多能够膨胀至其体积的1500倍。例如,在尿液条件下,输尿管支架可朝向输尿管壁膨胀和/或与输尿管壁接触以增强局部药物输送。由于可膨胀涂层可以施加在现有的常规支架上,这使得患者和从业者更加容易接受,因为那些使用支架的方案可以保持不变。有利地,支架组件在使用中能提供更大的通用性,因为,根据活性剂的位置,该活性剂可以以快速释放形式(当其被结合到可膨胀涂层中时)或者控制释放形式(当其被结合到载体中时)从支架组件中释放出来。
本文公开的支架组件包括支架。本文所用的术语“支架”是指假体,通常是细管,其可以是槽管、螺旋线圈或丝网管的形式,设计为插入待治疗的受试者(通常是哺乳动物如人、狗、小鼠、大鼠等)的血管或通道中,以保持该血管或通道为开放状态。
在具体实施例中,所述支架为输尿管支架。输尿管支架一般是指排尿装置,其促使尿液从肾脏通过输尿管排出到膀胱中。该支架可以是管状的,终止于两个相对端:远端(肾脏端)和近端(膀胱端)。支架的一端或两端部可以具有保持结构,例如图1所示的保持结构。
远端(肾脏端)保持结构被设计成将支架的远端保持在肾盂内,并且防止支架沿输尿管向下朝着膀胱移动,如图2所示。另一方面,近端(膀胱端)保持结构被设计成将支架的近端保持在膀胱内,并且防止支架沿输尿管向上朝着肾脏移动,如图2所示。
本发明的输尿管支架可被设计为插入输尿管中,以在患有输尿管狭窄、阻塞或创伤的患者体内形成从肾脏到膀胱的泌尿通道,或者在各种外科手术过程中保护输尿管的完整性。当用于此目的时,该支架允许尿液从肾脏正常流动。因此,支架可以具有中空的圆柱形构造。可以在长度、外径和壁厚方面为支架限定任何合适的尺寸,例如用作输尿管支架。
在一些实施例中,支架包括锥形端部,例如图17所示的端部。可以对支架施加锥形端设计以解决和/或减轻与涂层膨胀后支架的可移除性有关的问题。
尽管是针对上述功能设计的,但是本文公开的支架也可以用于其它应用或其他身体部位,例如但不限于用于治疗收缩的食管或胆管以保持其开放。
在各种实施例中,支架包括选自以下的材料:热塑性聚合物、弹性体聚合物、热塑性弹性体、其共聚物及其组合,其可以例如用于形成支架主体和保持结构。
在各种实施例中,支架可以包括以下物质或由以下物质组成:聚羧酸聚合物或共聚物,包括聚丙烯酸;缩醛聚合物和共聚物;丙烯酸酯和甲基丙烯酸酯和共聚物(例如甲基丙烯酸正丁酯);纤维素聚合物和共聚物;聚甲醛聚合物和共聚物;聚酰亚胺聚合物和共聚物如聚醚嵌段酰亚胺,聚酰亚胺,聚酯酰亚胺和聚醚酰亚胺;聚砜聚合物和共聚物,包括聚芳基砜和聚醚砜;聚酰胺聚合物和共聚物包括尼龙6,6,尼龙12,聚醚嵌段共聚酰胺聚合物(例如树脂树脂),聚己内酰胺和聚丙烯酰胺;聚碳酸酯;聚丙烯腈;聚乙烯吡咯烷酮;乙烯基单体的聚合物和共聚物,包括聚乙烯醇,聚氯乙烯,乙烯-乙酸乙烯酯共聚物(EVA),聚偏二氯乙烯,聚乙烯基醚如聚乙烯基甲基醚,乙烯基芳族聚合物和共聚物如聚苯乙烯,苯乙烯-马来酸酐共聚物,包括苯乙烯-丁二烯共聚物,苯乙烯-乙烯-丁烯共聚物(例如,作为KratonG系列聚合物获得的聚苯乙烯-聚乙烯/丁烯-聚苯乙烯(SEBS)共聚物)的乙烯基芳族烃共聚物,苯乙烯-异戊二烯共聚物(例如聚苯乙烯聚异戊二烯-聚苯乙烯),丙烯腈苯乙烯共聚物,丙烯腈-丁二烯-苯乙烯共聚物,苯乙烯-丁二烯共聚物和苯乙烯-异丁烯共聚物(例如聚异丁烯-聚苯乙烯嵌段共聚物如SIBS),聚乙烯基酮,聚乙烯基咔唑,和聚乙烯基酯如聚乙烯醋酸盐;聚苯并咪唑;离聚物;聚烷氧基聚合物和共聚物包括聚环氧乙烷(PEO);聚酯包括聚对苯二甲酸乙二醇酯,聚对苯二甲酸丁二醇酯和脂肪族聚酯,如丙交酯(包括乳酸以及d-,l-和内酰胺)的聚合物和共聚物,ε-己内酯,乙交酯(包括乙醇酸),羟基丁酸酯,羟基戊酸酯二恶烷酮,三亚甲基碳酸酯(及其烷基衍生物),1,4-二氧杂环庚烷-2-酮,1,5-二氧杂环庚烷-2-酮和6,6-二甲基-1,4-二恶烷-2-酮;包括聚芳醚如聚亚苯基醚,聚醚酮,聚醚醚酮的聚醚聚合物和共聚物;聚苯硫醚;聚异氰酸酯;聚烯烃聚合物和共聚物,包括聚亚烷基如聚丙烯,聚乙烯(低和高密度,低分子量和高分子量),聚丁烯(例如聚丁-1-烯和聚异丁烯),聚烯烃弹性体(例如,Santoprene),乙烯丙烯二烯单体(EPDM)橡胶,聚4-甲基-1-酮,乙烯-α-烯烃共聚物,乙烯-甲基丙烯酸甲酯共聚物和乙烯-乙酸乙烯酯共聚物;含氟聚合物和共聚物,包括聚四氟乙烯(PTFE),聚(四氟乙烯-共-六氟丙烯)(FEP),改性的乙烯四氟乙烯共聚物(ETFE)和聚偏二氟乙烯(PVDF);硅酮聚合物和共聚物;聚氨酯;对二甲苯聚合物;聚亚氨基碳酸酯;共聚(醚-酯)如聚环氧乙烷-聚乳酸共聚物;聚膦嗪;聚亚烷基草酸盐;聚氧酰胺和聚氧化酯(包括含有胺和/或酰氨基的那些);原酸酯;生物聚合物;以及上述的共混物和其它共聚物。聚氨酯(聚酯聚氨酯,聚醚聚氨酯,聚碳酸酯聚氨酯聚烯烃聚氨酯等),聚醚嵌段-聚酰胺共聚物(例如,可从Elf Atochem公司得到的商品名为PEBAX的聚[四氢呋喃]-b-聚酰胺-12嵌段共聚物),聚碳酸酯(例如双酚A聚碳酸酯),硅树脂(例如硅氧烷,如聚二甲基硅氧烷,聚二乙基硅氧烷,聚甲基乙基硅氧烷,聚甲基苯基硅氧烷和聚二苯基硅氧烷等等等,这些通常都是共价交联),聚四氟乙烯,和乙烯共聚物,如乙烯-乙酸乙烯酯共聚物(EVA),等等。
可膨胀涂层设置在支架的外表面的至少一部分上。如本文所用,术语“可膨胀涂层”是指由可膨胀材料形成的涂层,例如在液体如水性介质存在下能够膨胀或增加体积的材料。本文所用的术语“水性介质”和“水溶液”可互换使用,并且是指水或主要基于水的溶液,例如磷酸盐缓冲盐水(PBS)或其中溶解有盐的水。
例如,可膨胀材料可以吸收液体以导致膨胀或体积增加。本文公开的可膨胀涂层可以膨胀至其体积的1500倍。在各种实施例中,可膨胀涂层适于膨胀其体积的约5倍至约160倍。
用于形成可膨胀涂层的材料可具有吸收和释放大量液体介质的性质,从而显示出如在流体中的输送性质。可用于形成可膨胀涂层的合适材料可包括吸水膨胀性聚合物或超吸收性聚合物,其可在诸如水性介质的液体存在下膨胀。在一些实施例中,吸水膨胀性聚合物或超吸收性聚合物在交联后可归类为水凝胶。
在各种实施例中,可膨胀涂层包括可膨胀材料,其选自:水凝胶、吸水膨胀性聚合物、超吸收性聚合物、其共聚物及其组合。
在具体实施例中,可膨胀涂层包括或组成为水凝胶。如本文所公开的,术语“水凝胶”是指一类广泛的天然或合成的聚合物材料,其对水性介质具有亲和力,并且可以吸收大量的水性介质,但是其通常不溶解在水性介质中。
水凝胶通常可以通过使用至少一种或多种类型的水凝胶形成剂形成,并且在水性介质中一种或多种类型的水凝胶形成剂凝固或固化以形成三维网络,其中,三维网络的形成可能导致一种或多种类型的水凝胶形成剂凝胶化以形成水凝胶。术语“水凝胶形成剂”在本文中也称为“水凝胶前体”,是指可用于制备水凝胶的任何化合物。水凝胶形成剂可包括物理交联或化学交联的单体、均聚物、共聚物或其混合物。
包括水凝胶的可膨胀涂层的形成可以通过在溶液中向支架表面施加水凝胶形成剂,然后进行交联以获得可膨胀涂层。总吸收性和膨胀能力可以通过水凝胶中交联的类型和程度来控制。低密度交联水凝胶通常可以具有更高的吸收能力和更大程度的膨胀,而高密度交联水凝胶可能表现出较低的吸收能力和较小的膨胀。由于通过共价或非共价键形成交联网络结构,通常由亲水性有机聚合物组成的水凝胶可具有结构稳定性。
可以使用的合适水凝胶的实例包括由水凝胶形成剂制得的水凝胶、如聚乙烯醇、聚二醇如聚乙二醇二甲基丙烯酸酯、聚乙二醇二丙烯酸酯、丙烯酰胺、聚丙烯酸、水解聚丙烯腈、聚乙烯亚胺、乙氧基化聚乙烯亚胺聚烯丙胺和聚二醇制成的水凝胶、阴离子聚合物如透明质酸、甲基丙烯酸化透明质酸(HAMA)、阳离子聚合物如壳聚糖、两亲性聚合物如胶原、明胶和纤维蛋白、中性聚合物如葡聚糖和琼脂糖、以及上述各项的单体、上述各项的的低聚物、上述各项的的大分子单体、上述各项的的共聚物和/或上述各项的衍生物。
在一些实施例中,可膨胀涂层包括由聚(乙二醇)二丙烯酸酯(PEGDA)、甲基丙烯酸化透明质酸或其组合制成的水凝胶。
另外,或者除了上述之外,水溶性聚合物和非水溶性前体的各种组合形成的互穿聚合物网络,以及具有用钙或磷酸酯衍生物改性的骨架的聚合物也可以适用于某些实施例。
在一些实施例中,例如图3所示的实施例,设置在支架的外表面的至少一部分上的可膨胀涂层在尿液状态下向输尿管壁膨胀并与其接触。由于可膨胀涂层与输尿管壁的直接接触,这允许活性剂局部输送到受试者中。如本文所用,术语“受试者”通常指任何宿主、动物、脊椎动物或无脊椎动物,并且包括鱼、哺乳动物、两栖动物、爬行动物、鸟类、特别是人。在具体实施例中,例如图4所示的实施例,将活性剂直接负载到可膨胀涂层中,以使活性剂快速释放到预期的输送部位。
如本文所用,术语“活性剂”通常是指引发如上所定义的受试者的生物反应的分子、化合物或组合物。例如,活性剂可以是提供一些药理作用的药剂,通常是有益的,并且在一些实施例中可以是能够治疗、抑制或预防失调或疾病。
活性剂的实例包括治疗剂、药剂、药物(例如治疗化合物,药用盐)、非药物(例如化妆品物质)、疫苗、免疫剂、局部或全身麻醉剂或止痛药、抗原或蛋白质或肽,例如胰岛素、化学治疗剂或抗肿瘤剂、活性剂的药理学活性盐、活性剂的药学上可接受的盐、活性剂的前体活性剂、代谢物、类似物等等。
在一些实施例中,活性剂选自抗纤维化剂、抗癌剂、不适减轻剂、抗菌剂、基因、基因载体、生长因子及其组合。
术语“抗纤维化剂”是指在哺乳动物中具有抗纤维化活性的一种或多种化学或生物化合物。这些化合物可以具有不同的作用机制,例如,一些可以通过减少胶原蛋白或另一种蛋白质的形成而起作用,而另一些可通过增强新陈代谢或去除身体受影响区域中的胶原蛋白而起作用。所有这些在减少纤维组织的存在中具有活性的化合物都适合用作本文公开的抗纤维化剂,而不考虑化合物起作用的特定作用机理。
抗纤维化剂的具体实例包括丝裂霉素-C、5-氟尿嘧啶、雷帕霉素、转化生长因子(TGF)抗体、免疫抑制剂和肝素。转化生长因子(TGF)抗体可以选自TGF-B2单克隆抗体、白细胞介素1或6抗体和细胞因子抗体,免疫抑制剂可以选自环孢菌素和FK57。
在一些实施例中,所述抗纤维化剂选自:抗纤维化药物,如丝裂霉素-C、5-氟尿嘧啶或雷帕霉素;转化生长因子(TGF)抗体,如TGF-B 2单克隆抗体、白细胞介素1或6抗体;免疫抑制剂,如环孢菌素或FK57;肝素;及其组合。
如本文所用,术语“抗癌剂”是指可以杀死癌细胞或抑制癌细胞功能的化合物或物质。抗癌剂包括烷基化剂,如三氯乙胺、亚硝基脲(卡莫司汀,洛莫司汀)、美法仑、环磷酰胺、白消安和丙卡巴肼,抗代谢药如甲氨蝶呤、6-硫鸟嘌呤、5-氟尿嘧啶、6-巯嘌呤、阿糖胞苷、吉西他滨、氟达拉滨和卡培他滨,激素如长春新碱、长春花碱、紫杉醇和多西紫杉醇,激素如雌激素、泼尼松、戈舍瑞林、抗雌激素(他莫昔芬)、氟他胺、亮丙瑞林,免疫抑制剂如硫唑嘌呤、他克莫司(FK506)、环孢菌素a,天然产物如放线菌素,博来霉素、喜树碱和类似物(例如伊立替康和托泊替康)、柔红霉素、丝裂霉素C、多柔比星、依托泊苷(V P-16)和其他试剂如羟基脲、天冬酰胺酶、安吖啶、顺铂、卡铂、米托蒽醌和伊马替尼。
在一些实施例中,抗癌剂选自:烷基化剂,如氮芥、亚硝基脲(卡莫司汀、洛莫司汀)、美法仑、环磷酰胺、白消安或甲基苄肼;抗代谢物,如甲氨蝶呤、6-硫鸟嘌呤、5-氟尿嘧啶、6-巯基嘌呤、阿糖胞苷、吉西他滨、氟达拉滨或卡培他滨;抗有丝分裂剂,如长春新碱、长春花碱、紫杉醇或多西他赛;激素,如雌激素、泼尼松、戈舍瑞林,抗雌激素(他莫昔芬)、氟他胺或亮丙瑞林;免疫抑制剂,如硫唑嘌呤、他克莫司(FK506)或环孢菌素a、更生霉素、博来霉素、喜树碱和类似物(如伊立替康和托泊替康),柔红霉素、丝裂霉素C、多柔比星、依托泊苷(V P-16)、羟基脲、天冬酰胺酶、安吖啶、顺铂、卡铂、米托蒽醌、伊马替尼;及其组合。
不适减轻剂可以起到减轻受试者的疼痛和/或不适的作用。不适减轻剂包括解痉剂,如阿利苯醇、氨布醋胺、氨丙嗪、阿朴阿托品、甲硫贝弗宁、比他维林、布他维林、溴丁托品、丁溴东莨菪碱、卡罗维林、西托溴铵、桂麻磺碱、氯波必利、氢溴酸欧毒芹硷、盐酸毒芹碱、碘化环宁、双苯美林、地索普明、吗苯丁酯、地泊溴铵、六氢芬宁、依美溴铵、乙基罂粟碱、非克立明、非那拉胺、非诺维林、芬哌丙烷、fenpiver inium bromide、芬托溴铵、黄酮哌酯、夫洛丙酮、葡(萄)糖酸、愈创他明、肼双二乙氨三嗪、羟甲香豆素、利奥吡咯、甲苯凡林、莫沙维林、萘维林、辛戊胺、奥他维林、盐酸奥昔布宁、戊哌立特、phenamacide hydrochloride、间苯三酚、匹维溴铵、哌苯乙醇、盐酸吡哆醇、普拉维林、溴化丙啶、丙哌利定、丙酰胺、丙嗪、普罗扎平、消旋非明、罗西维林、解痉醚、司洛碘铵、舒托泊铵、替莫碘胺、替喹溴胺、替瑞酰胺、曲匹布通、tricromyl、trifolium、曲美布汀、N、N-三甲基-3、3二苯基丙胺、甲氧莨菪醇二苯乙醇酸酯、曲司氯铵和珍托溴铵,等等,以及它们的组合和药学上可接受的盐;α-肾上腺素能阻滞剂,例如阿夫唑嗪、缩水甘油、阿莫西林、达哌拉唑、多沙唑嗪、甲磺酸麦角酰酯、芬太尼、异唑、吲哚满胺、拉贝洛尔、马替泊、萘非那韦、麦角林、哌唑嗪、坦索罗辛、特拉唑嗪、甲苯唑啉、三甲氧唑嗪和育亨宾。
其中,坦索罗辛、阿夫唑嗪、多沙唑嗪、哌唑嗪、坦索罗辛和特拉唑嗪均为α-1-肾上腺素能阻滞剂,坦索罗辛和阿夫唑嗪均为选择性α-肾上腺素能受体阻滞剂。
不适减轻剂的其它实例包括皮质类固醇,例如倍他米松、可的松、地塞米松、灭斑角、氢化可的松、甲基强的松龙、泼尼松龙、强的松和曲安奈德;麻醉止痛剂,包括可待因、吗啡、芬太尼、哌替啶、丙氧芬、左啡诺、羟考酮、羟吗啡酮、氢吗啡酮、喷他佐辛和美沙酮;非麻醉止痛剂、包括对乙酰氨基酚和非类固醇消炎药如阿司匹林、二氟尼柳、噻吗化合物、布洛芬、酮洛芬、萘普生、吲哚美辛、塞来昔布、伐地考昔、双氯芬酸、依托度酸、非诺洛芬、氟比洛芬、酮咯酸、萘丁美酮、萘普生、奥沙普秦、吡罗昔康、舒林酸、托美丁和伐地考昔;包括苯佐卡因、可卡因、利多卡因、三氯生、甲哌卡因和诺瓦卡因等局部麻醉剂,以及上述的组合和药学上可接受的盐,酯和衍生物。
在一些实施例中,不适减轻剂选自解痉剂、α-肾上腺素能阻滞剂、皮质类固醇、麻醉止痛剂、非麻醉止痛剂、非甾体抗炎药、局部麻醉剂、其组合,其药学上可接受的盐,其酯及其衍生物。
本文所用术语“抗菌剂”,也称为“抗生素剂”是指能够抑制、减少或预防细菌生长以及降低细菌感染性或毒性的化合物或物质。抗菌剂的实例包括但不限于丝裂霉素C、博来霉素、更生霉素、培养霉素和蒽环类药物如多柔比星、柔红霉素、表柔比星、伊达比星或蒽二酮。
在具体实施例中,活性剂是丝裂霉素C、紫杉醇、三氯生或其组合。
可膨胀涂层可以设置在支架的外表面的至少一部分上。在一些实施例中,可膨胀涂层设置在支架的大部分或基本全部外表面上。本文所用的术语“外表面”是指支架的外表面,相对于血管腔内部空间。
可选地,支架组件包括分散在可膨胀涂层中和/或设置在支架外表面的至少一部分的载体上。本文所用术语“载体”,其他称为“输送剂”是指有用和/或有效输送特定或期望活性剂的任何载体化合物或试剂。当存在载体时,载体可以分散在可膨胀涂层中和/或设置在支架的外表面的至少一部分上。
载体可以由各种合适的材料形成,包括所有聚合物材料。在一些实施例中,载体可包括或组成为可生物降解聚合物。在一些实施例中,载体由可生物降解聚合物形成。术语“可生物降解的”、“可生物吸收的”和“可生物再吸收的”在本文中可互换使用,并且通常指通过微生物分解或当暴露于大自然中常见的环境条件时在相对短的时间内(2-15个月内)自发分解的物质。
可以被认为可生物降解的聚合物的实例包括脂族聚酯、聚(氨基酸)、共聚(醚-酯)、聚亚烷基草酸酯、聚酰胺、聚(亚氨基碳酸酯、聚原酸酯、聚氧酯、聚酰胺酯、含有酰氨基的聚氧化酯、聚(酸酐)、聚磷腈、聚碳酸酯,天然存在的可生物降解聚合物如壳聚糖、胶原、淀粉及其共混物。聚原酸酯的实例包括聚丙交酯、聚乙交酯、聚己内酯、聚乳酸、可生物降解的聚酰胺、可生物降解的脂族聚酯和/或其共聚物,或其它可生物降解的聚合物,如上述那些。
在一些实施例中,可生物降解聚合物选自聚己内酯(PCL)、聚(D,L-丙交酯-co-己内酯)(PLC)、聚-L-丙交酯(PLLA)、聚-D-丙交酯(PDLA)、聚乙交酯(PGA)、聚乳酸(PLA)、聚己内酯-聚乳酸共聚物(PCL-PLA共聚物)、聚丙交酯-聚乙交酯共聚物(PLGA)、聚(碳酸三亚甲基酯)、聚己内酯(PCL)和聚(三亚甲基碳酸酯)(TMC)的共聚物;聚乳酸(PLA)、聚己内酯(PCL)和/或聚(三亚甲基碳酸酯)(TMC)的三嵌段共聚物;聚乳酸-聚环氧乙烷共聚物、聚葡萄糖酸聚羟基丁酸酯、聚酐、聚磷酸酯、聚(氨基酸)、聚二恶烷酮、纤维素、胶原、壳聚糖,其共聚物及其组合。
在具体实施例中,载体包含选自聚-L-丙交酯-co-己内酯、聚丙交酯-聚乙交酯共聚物,其共聚物及其组合的材料。
载体可以作为一个或多个颗粒和/或一个或多个层设置在:(a)支架和可膨胀涂层之间,(b)可膨胀涂层内,和/或(c)可膨胀涂层上。载体可以是例如设置在支架和可膨胀涂层之间的单层或多层薄的聚合物涂层。有利地,这使得包含在载体中的活性剂更均匀地受控释放。
在一些实施例中,载体包含颗粒。载体颗粒设置在支架和可膨胀涂层之间,在可膨胀涂层内,和/或在可膨胀涂层上。在一些实施例中,包括颗粒的载体设置在可膨胀涂层内。
颗粒尺寸范围可以在约20nm至约1000nm,或约1000nm至1000μm,更典型地,约20nm至约100μm,或约100nm至约100μm。例如,颗粒尺寸范围可以在约200nm至约100m,如约500nm至约100m,约800nm至约100m,约1m至约100m,约20m至约100m,约50m至约100m,约75m至约100m,约100nm至约80m,约100nm至约60m,约100nm至约40m,约100nm至约20m,约100nm至约1m,约1m至约50m,或约10m至约60m。
在一些实施例中,载体作为设置在支架的外表面的至少一部分上的一个或多个层存在。例如,包含载体的一个或多个层可以设置在支架和可膨胀涂层内,在可膨胀涂层之间和/或在可膨胀涂层上。
一个或多个层的厚度可以在约1m至约3000m的范围内,更典型地,在约10m至约1000m的范围内。例如,一个或多个层的厚度范围可以在约10m至约1000m。例如,一个或多个层的厚度范围可以在约50μm至约1000μm,例如约100μm至约1000μm,约300μm至约1000μm,约500μm约10μm至约1000μm,约750μm至约1000μm,约10μm至约800μm,约10μm至约600μm,约10μm至约500μm,约10μm至约500μm约50μm至约800μm,约100μm至约500μm。
在具体实施例中,载体作为设置在支架和可膨胀涂层之间的一个或多个层存在。一个或多个层可以包括或组成为热塑性弹性体,例如苯乙烯嵌段共聚物、聚烯烃共混物、弹性体合金、热塑性聚氨酯、热塑性共聚酯和热塑性聚酰胺。更具体的实例包括聚酯基聚氨酯、聚醚基聚氨酯、聚烯烃基聚氨酯、聚酯-聚醚共聚物如聚[对苯二甲酸二甲酯]-聚[四亚甲基醚二醇]嵌段共聚物、和聚[对苯二甲酸丁二醇酯]-聚[四氢呋喃]嵌段共聚物、和聚苯乙烯-聚烯烃嵌段共聚物如聚(苯乙烯-b-聚乙烯/丁烯-b-聚苯乙烯)(SEBS)、和聚(苯乙烯-b-异丁烯-b-苯乙烯)三嵌段共聚物(SIBS)、和聚醚-聚酰胺嵌段共聚物如聚[四氢呋喃]-嵌段-聚酰胺-12嵌段共聚物。
包含在所述一个或多个层中的热塑性弹性体可以具有与支架中包含的材料(例如支架主体和/或保持结构)至少相同或更高的断裂伸长率。
目前可获得的大多数生物可吸收聚合物,如聚乳酸(PLA)、聚己酸内酯(PCL)和聚乳酸-co-乙醇酸(PLGA)显示出非常相似的机械性能,具有高杨氏模量和较低的断裂伸长率。有时候,这些聚合物处于纯粹形式,看似不适合使用,因为临床需要高度柔性材料。在一些实施例中,一种或多种上述聚合物可以与另一种聚合物共混或与另一种聚合物共聚,其中共聚可以促进获得宽范围的性质,包括良好的机械强度、生物相容性、可生物降解性和可加工性,以使聚合物称为于医疗应用的优良材料。
活性剂包含在至少一种可膨胀涂层或载体中(如果有)。如上所述,在不存在载体的实施例中,活性剂仅包含在可膨胀涂层中。负载在可膨胀涂层中的活性剂可以被输送到受试者的预期部位以允许活性剂快速释放到受试者。
在存在载体的实施例中,至少一部分活性剂可包含在载体中,用于从载体中受控释放活性剂。这意味着活性剂可以包含或存在于可膨胀涂层和载体中。通过将活性剂负载到可膨胀涂层和载体中,可以增加活性剂在支架组件中的负载。负载在可膨胀涂层中的活性剂可以不同于负载在载体中的活性剂,这反过来允许根据施用的受试者定制活性剂。在进一步的实施例中,活性剂可以仅包含在载体中。活性剂负载的广泛性允许定制支架组件以适应患者的个体需要和支架的预期应用要求。
载体中活性剂的量范围可以在载体的约2wt%至5wt%。例如,载体中活性剂的量范围可以在约3wt%至约25wt%,约5wt%至约25wt%,约7wt%至约25wt%,约12wt%约25wt%,约18wt%至约25wt%,约2wt%至约18wt%,2wt%至约10wt%,约2wt%至约6wt%,约2wt%约5wt%至约20wt%,约9wt%至约18wt%,约3wt%至约8wt%,约4wt%至约6wt%,或约4wt%%至约9wt%。
各个实施例在另一方面涉及使用根据第一方面的支架组件作为输尿管支架。
如上所述,本文公开的支架组件能够抑制输尿管成纤维细胞增殖,以防止狭窄复发。当与液体介质接触时最多能够膨胀至其体积的1500倍的可膨胀涂层设置在支架的外表面的至少一部分上。一种或多种活性剂可以引入可膨胀涂层中。例如,在尿液条件下,输尿管支架膨胀可朝向和/或与输尿管壁接触以增强局部活性剂输送。另外或替代地,载体可以包含在支架组件中,使得通过在载体中引入活性剂,可以控制释放活性剂。由于可膨胀的涂层可以施加在现有的常规支架上,所以因为使用支架的方案可以保持不变,从而为患者和从业者提供了更容易接受的方案。有利地,支架组件在使用中提供更大的通用性,因为取决于活性剂的位置,活性剂可以以快速释放形式(当其结合到可膨胀涂层中时)或者以控制释放形式(当它被并入载体时)从支架组件中移除。
在第三方面,提供制备支架组件的方法。该方法包括提供支架。可以使用的合适的支架已经在上面讨论过。
在各种实施例中,提供支架包括以下至少其中一项:物理处理或化学处理支架的外表面。
物理地处理支架的外表面可以包括使支架的外表面纹理化,例如赋予表面拓扑结构或图案。在这样做时,可以在支架表面上形成物理结合部位,这可以改善支架表面和可膨胀涂层之间的物理键合或黏附。在一些实施例中,通过诸如湿法或干法蚀刻的蚀刻,和/或用固体颗粒粗糙化外表面来进行支架外表面的纹理化。
可以通过等离子体处理对支架的外表面进行化学处理。通过等离子体涂覆表面,可形成化学键合位点。在各种实施例中,等离子体处理包括氧等离子体的第一步骤和氮等离子体的第二步骤。通过进行等离子体处理,可以将亲水的伯和/或仲氨基固定在支架的表面上,以允许与包含在可膨胀涂层中的可膨胀材料的官能团相互作用或结合。
在各种实施例中,氧等离子体的第一步骤可以涉及化学氧化处理,或者将支架表面暴露于含氧气体,可选地在氩(Ar)和/或其它惰性气体中,以产生自由基。
氮等离子体的第二步骤可以涉及将支架表面暴露于含有氮原子的等离子体气体中以形成氨基。含有氮原子的合适的等离子体气体的实例包括氨、伯胺和仲胺、一氧化二氮、氮、含氮部分的其它气体,以及这些气态化合物的混合物。
制备支架组件的方法包括在支架上设置可膨胀材料。可膨胀材料可以设置在经物理和/或化学处理的支架表面上,从而含有合适的物理结合位点和/或化学键合位置。可以使用的合适的支架的实例已经在上面讨论过。
将可膨胀材料设置在支架上;非必要性地,包括将载体分散在可膨胀材料中和/或将载体设置在支架的外表面的至少一部分上;并将活性剂并入可膨胀材料或载体,如果载体存在的话,中的至少其中一个内,以在支架的外表面的至少一部分上形成可膨胀涂层。可以使用的合适的载体的实例已经在上面讨论过。
在一些实施例中,将可膨胀材料设置在支架上包括在支架的外表面的至少一部分上施加包含可膨胀材料和活性剂的液体试剂。如上所述,活性剂可以仅包含在或可掺入到可膨胀涂层中,例如在不存在载体或载体未负载活性剂的情况下。负载在可膨胀涂层中的活性剂可以被输送到受试者的预期部位以允许活性剂快速释放到受试者。
可膨胀材料或载体(如果存在)的至少其中一个中并入活性剂,以在支架外表面的至少一部分上形成可膨胀涂层。合适的活性剂的实例已经在上面讨论过。
在各种实施例中,将可膨胀材料设置在支架上包括将载体分散在可膨胀材料中和/或在支架的外表面的至少一部分上设置载体。
在一些实施例中,制备支架组件的方法包括将活性剂掺入可膨胀材料和载体中。在具体实施例中,制备支架组件的方法包括仅将活性剂掺入载体中。如上所述,活性剂可以掺入到可膨胀材料中,例如通过在形成可膨胀涂层之前将活性剂分散在包含可膨胀材料的悬浮液或溶液中。同样地,将活性剂并入载体中可以包括将活性剂分散在包含载体的悬浮液或溶液中,以将活性剂分散在载体中或将活性剂涂覆在载体上,随后形成载体。
将可膨胀材料置于支架上可以通过选自喷雾、刷涂、浸涂、模塑、电沉积及其组合的方法进行。
在一些实施例中,可膨胀材料包含水凝胶或由水凝胶组成。将可膨胀材料置于支架上还可包括使水凝胶形成剂交联,以形成水凝胶。合适的水凝胶形成剂的实例已经在上面讨论过。合适的交联技术的实例包括物理交联、化学交联、辐射交联或其组合。
物理交联可以通过例如络合、氢键合、去溶剂化、范德华相互作用或离子键合进行。在各种实施例中,可以通过在水性介质中的一种或多种类型的水凝胶形成剂的自组装来形成水凝胶。术语“自组装”是指通过依赖于组分彼此的吸引力以及组分之间没有化学键形成而自发组织较高级结构的组分的过程。例如,聚合物链可以通过在聚合物链上诱导的疏水力、氢键、范德华相互作用、静电力或聚合物链缠结中的任何一种彼此相互作用,使得聚合物链在水性介质中聚集或凝结以形成三维网络,从而截留水分子以形成水凝胶。可以使用的物理可交联聚合物的实例包括但不限于明胶、藻酸盐、果胶、呋喃菌素、角叉菜胶聚糖、壳聚糖,其衍生物,其共聚物及其混合物。
化学交联可能在化学交联剂存在下进行。在一些实施例中,通过使水凝胶形成剂与交联剂接触来进行水凝胶形成剂的交联。术语“化学交联剂”是指诱导化学交联的试剂。化学交联剂可以是任何能够诱导相邻聚合物链之间的化学键的试剂。例如,化学交联剂可以是化合物。可用作交联剂的化合物的实例包括但不限于1-乙基-3-[3-二甲基氨基丙基]碳二亚胺盐酸盐(EDC)、乙烯基胺、甲基丙烯酸2-氨基乙酯、3-氨基丙基甲基丙烯酰胺、乙烯二甲基丙烯酸酯、N、N'-亚甲基双丙烯酰胺、N、N'-亚甲基双-甲基丙烯酰胺、二烯丙基二甲基丙烯酰胺、(甲基)丙烯酸烯丙酯、低级亚烷基二醇二(甲基)丙烯酸酯、(甲基)丙烯酸酯、低级亚烷基二(甲基)丙烯酸酯、二乙烯基醚、二乙烯基砜、二或三乙烯基苯、三羟甲基丙烷三(甲基)丙烯酸酯、季戊四醇四(甲基)丙烯酸酯、双酚A二(甲基)丙烯酸酯、亚甲基双(甲基)丙烯酰胺、邻苯二甲酸三烯丙酯、邻苯二甲酸二烯丙酯、转谷氨酰胺酶,其衍生物或其混合物。
在一些实施例中,水凝胶形成剂本身能够在不使用交联剂的情况下进行化学或物理交联。
除了上述之外,水凝胶形成剂可以使用电磁波形式的交联剂进行交联。交联可以使用如伽马或紫外线辐射的电磁波来进行,其可使聚合物链交联并形成三维基底,由此截留水分子形成水凝胶。可膨胀材料还可以包含光引发剂以允许通过照射进行交联。光引发剂的实例是可从Ciba Specialty Chemicals获得的IRGA CURE品牌引发剂。
因此,交联剂的选择取决于存在的聚合物链和官能团的类型,本领域技术人员将能够相应地选择合适类型的交联剂。
在各种实施例中,通过用电磁辐射照射水凝胶形成剂来进行水凝胶形成剂的交联。可以使用的电磁辐射的实例包括无线电波、微波、太赫兹辐射、红外辐射、如可见光、紫外光和红外光的光,X射线和伽马射线。在一些实施例中,电磁辐射是紫外线或蓝光,在本文中统称为“UV/Vls辐射”,其可以具有在约240nm至约380nm范围内的波长。在具体实施例中,电磁辐射具有约365nm的波长。
用电磁辐射辐射水凝胶形成剂可以在任何合适的时间段内进行。电磁辐射可以进行约1分钟至约15分钟,例如约5分钟至约15分钟,约8分钟至约15分钟,约10分钟至约15分钟,约1分钟至约12分钟,约1分钟至约8分钟,或约8分钟至约12分钟。
下文中,将参考附图,并展示示范性实施例,来全面叙述本发明。但是,本发明可以实现为为许多不同的形式,且不应被解释为限于本文所阐述的示例性实施例中。相反,提供所述实施例是为了使得本公开彻底和完整,并且向本领域技术人员所熟知充分表达本发明的范围。在附图中,为了清楚起见,层和区域的长度和尺寸可能被放大。
本申请中所用的术语“和/或”涵盖一种或多种相关列举项目的所有组合。本申请说明性地描述的发明可以适当地在去掉任何一种或多种本申请未具体公开的要素或限定后实施。因此,例如,术语“包含”、“包括”、“含有”等应当作非限制性的广义理解。另外,本申请所用的术语和表达是描述性而非限制性的,且使用所述术语和表达无意排除所述和所示的特征的任何等同形式或其部分,但是,应当理解,还可以在所述发明的范围内,对其进行各种改进。因此,应该理解的是,尽管公开了本发明的优选实施例和可选特征,本领域技术人员仍可以对本申请所公开的发明进行改进和变形,且所述改进和变形应当看作是包含在本发明的范围之内。
本申请对本发明进行了广泛的一般性描述。在此广泛公开范围中的每种较窄的种类和亚属分类均构成本发明的一部分。这包括本发明中带有从属类中排除任何主题的附带条件或否定性限制的一般描述,无论所去除内容是否在本申请中具体列举。
以下权利要求及非限制性实施例中为其他实施例。此外,当以马库什组来描述本发明的特征或方面时,本领域的技术人员能够理解,本发明也由此在马库什组的任何单个成员或成员的亚组中进行了描述。
实验部分
本文公开的各种实施例涉及改进输尿管支架,其目的是抑制输尿管成纤维细胞增殖以防止狭窄复发。本文所述的支架包括可膨胀涂层,当与介质接触时,其最多可以膨胀达其体积的1500倍,更通常为其体积的5至160倍。有利地,输尿管支架可以在尿液条件下膨胀可朝向输尿管壁膨胀和/或与接触,以增强局部药物输送。可膨胀涂层可以施加在现有的常规支架上。介质可以包含至少一种泌尿有益剂,例如抗纤维化药物。在一些实施例中,可膨胀涂层还包含至少一种聚合物输送平台,在本文中另外称为载体。聚合物递送平台可以与泌尿有益剂联合起作用,本文另外称为活性剂,以控制药剂的释放。
水凝胶膨胀可用于增强药物局部输送到组织中。药物可以是抗纤维化药、抗菌药、抗癌药或具有两种或更多的上述性质的多功能药物。可以通过简单地移除支架来终止治疗涂层可以施加到任何市售的输尿管支架表面上。有利地,本文公开的改进的输尿管支架不会对已建立的医师实践/工作流程产生破坏性,并且不需要新的技能或医保报销代码。
本文还公开了可以表现上述膨胀特性的涂覆输尿管支架的制造方法。该方法可以包括以下步骤:物理处理支架表面以在支架的表面上形成物理键合,化学处理表面以在支架的表面上形成化学键合,用水凝胶涂覆修饰表面,并将水凝胶交联在药物洗脱层上形成水凝胶涂层以形成可膨胀涂层。
在各种实施例中,该方法包括用包括泌尿有益剂的可膨胀层涂覆输尿管支架。在一些实施例中,该方法包括掺入负载有泌尿生物有益剂的药物输送平台。
有利的是,具有独特可膨胀涂层的输尿管支架能够在尿液状态下膨胀,这有助于有效地增强局部药物递送,从而增加治疗效果。此外,独特的可膨胀涂层可以容易地应用于任何市售的的输尿管支架表面,而不需要增加成本地生产特殊的支架和输送系统。通过移除支架可以容易地终止治疗。此外,本文公开的可膨胀涂层输尿管支架可以容易地应用于目前的实践中,并且预期泌尿科医师和患者容易地接受,因为使用的支架和使用的程序/方案不变。
实施例1
在第一实施例中,将7.5%的丝裂霉素C(MMC)掺入到聚-L-丙交酯-co-己内酯(PLC70/30)中。然后将该制剂涂覆到支架上作为药物输送涂层。然后用氧气对药物涂层支架进行5分钟的等离子体处理,处理条件为100W、30秒。最后,将7.5%PEGDA和0.2%Irgacure的水溶液涂覆到等离子体改性过的药物涂层支架上,将该支架以1cm的距离暴露于365nm的紫外光(6W)中5分钟,同时手动地缓慢旋转该支架。
均匀的药物输送涂层和可膨胀涂层可以在pH为6至8.5的各种尿液条件下控制MMC在28天内的释放,如图7所示。
实施例2
在第二实施例中,用氧气对聚氨酯支架进行5分钟的等离子体处理,处理条件为100W、2分钟。将10%的紫杉醇预加载到PLGA颗粒中,然后与1%甲基丙烯酸化透明质酸(HAMA)溶液和2%Igacure水溶液混合,涂覆到等离子体处理过的支架表面上,暴露于365nm紫外光15分钟。如图8所示,涂层表面光滑。
实施例3
在第三实施例中,将5%的5-氟尿嘧啶负载到聚-L-丙交酯-co-己内酯溶液中,涂覆到支架上以形成药物输送涂层。将10%三氯生预先加载到PLGA颗粒中,与5%PEGDA溶液和0.1%Igacure水溶液混合,涂覆到装载有5-氟尿嘧啶的PLC的预处理表面上,暴露于365nm紫外光10分钟。
实施例4:细胞工作
在96孔细胞培养板的每个孔中,接种3000个人膀胱基质成纤维细胞。接种一天后,将不同浓度的溶解在细胞培养基(200μL)中的丝裂霉素C加入孔中。药物治疗3天后,除去药物培养基,并加入9:1(细胞培养基:prestoblue)比例的70微升细胞活力试剂。发现造成人膀胱基质成纤维细胞死亡的MMC的最低浓度为0.01μg/mL,即需要0.01μg/mL的MMC来抑制成纤维细胞增殖。在10-0.94μg/mL或约0.115μg/mL测量GI50。
实施例5:MMC洗脱输尿管支架对成纤维细胞抑制的影响
对于24孔细胞培养板的每个孔,接种12000个人膀胱基质成纤维细胞。在接种1天后,将各支架样品置于孔中的细胞培养插入物中,使得支架与细胞之间没有直接接触。在此之前,将支架用环氧乙烷气体灭菌。发现支架(聚氨酯),聚合物和水凝胶不会影响或抑制成纤维细胞,而药物涂层支架能够显著降低细胞的增殖。与样品4相比,样品5的细胞增殖抑制略高,这是由于水凝胶涂层支架在最初几个小时内释放的药物量较多。
尽管本发明中描述了具体细节并引用了示例实施例,但是本领域技术人员可以理解,可以在不脱离本发明如下列权利要求所限定的范围和思路的前提下,对本发明进行形式和细节上的各种改变。
Claims (36)
1.一种支架组件,由以下各项组成:
a)支架,其是管或螺旋线圈;
b)载体,其包含第一活性剂,其中所述载体设置为直接在所述支架的外表面的至少一部分上的一层或多层;和
c)可膨胀涂层,其包括第二活性剂,其中所述可膨胀涂层设置在所述一层或多层的载体的至少一部分上,所述可膨胀涂层适于膨胀其体积的约5倍至约160倍。
2.根据权利要求1所述的支架组件,其特征在于,所述支架包括选自以下各项的材料:热塑性聚合物、弹性体聚合物、热塑性弹性体、其共聚物及其组合。
3.根据权利要求1所述的支架组件,其特征在于,所述可膨胀涂层包括选自水凝胶、吸水膨胀性聚合物、超吸收性聚合物、其共聚物及其组合的可膨胀材料。
4.根据权利要求3所述的支架组件,其特征在于,所述可膨胀涂层包含水凝胶或由水凝胶组成。
5.根据权利要求4所述的支架组件,其特征在于,所述水凝胶包括以下材料制成的水凝胶,或由以下材料制成的水凝胶构成:聚乙烯醇、聚乙二醇、聚乙二醇二甲基丙烯酸酯、聚(乙二醇)二丙烯酸酯、丙烯酰胺、聚丙烯酸、水解聚丙烯腈、聚乙烯亚胺、乙氧基化聚乙烯亚胺聚烯丙基胺、透明质酸、甲基丙烯酸化的透明质酸、壳聚糖、胶原、明胶、纤维蛋白、葡聚糖、琼脂糖、以上各项的单体、以上各项的低聚物、以上各项的大分子单体、以上各项的共聚物、以上各项的衍生物或其组合。
6.根据权利要求5所述的支架组件,其特征在于,所述可膨胀涂层包含水凝胶,该水凝胶由聚(乙二醇)二丙烯酸酯、甲基丙烯酸化透明质酸或其组合制成。
7.根据权利要求1所述的支架组件,其特征在于,所述第一活性剂和所述第二活性剂选自抗纤维化剂、抗癌剂、不适减轻剂、抗菌剂、基因、基因载体、生长因子及其组合。
8.根据权利要求7所述的支架组件,其特征在于,所述抗纤维化剂选自:抗纤维化药物,如丝裂霉素-C、5-氟尿嘧啶或雷帕霉素;转化生长因子(TGF)抗体,如TGF-B 2单克隆抗体、白细胞介素1或6抗体;免疫抑制剂,如环孢菌素或FK57;肝素;及其组合。
9.根据权利要求7所述的支架组件,其特征在于,所述抗癌剂选自:烷基化剂,如氮芥、亚硝基脲(卡莫司汀、洛莫司汀)、美法仑、环磷酰胺、白消安或甲基苄肼;抗代谢物,如甲氨蝶呤、6-硫鸟嘌呤、5-氟尿嘧啶、6-巯基嘌呤、阿糖胞苷、吉西他滨、氟达拉滨或卡培他滨;抗有丝分裂剂,如长春新碱、长春花碱、紫杉醇或多西他赛;激素,如雌激素、泼尼松、戈舍瑞林,抗雌激素(他莫昔芬)、氟他胺或亮丙瑞林;免疫抑制剂,如硫唑嘌呤、他克莫司(FK506)或环孢菌素a、更生霉素、博来霉素、喜树碱和类似物(如伊立替康和托泊替康),柔红霉素、丝裂霉素C、多柔比星、依托泊苷(V P-16)、羟基脲、天冬酰胺酶、安吖啶、顺铂、卡铂、米托蒽醌、伊马替尼;及其组合。
10.根据权利要求7所述的支架组件,其特征在于,所述不适减轻剂选自:解痉剂、α-肾上腺素能阻滞剂、皮质类固醇、麻醉止痛剂、非麻醉止痛剂、非甾体抗炎药、局部麻醉剂、其组合、其药学上可接受的盐、其酯及其衍生物。
11.根据权利要求1所述的支架组件,其特征在于,所述第一活性剂和第二活性剂为丝裂霉素C、紫杉醇、三氯生或其组合。
12.根据权利要求1所述的支架组件,其特征在于,所述活性剂在所述载体中的量占所述载体的约2wt%至约25wt%。
13.根据权利要求1所述的支架组件,其特征在于,所述载体包括可生物降解聚合物,或由可生物降解聚合物组成。
14.根据权利要求13所述的支架组件,其特征在于,所述可生物降解聚合物选自:聚己内酯(PCL)、聚(D,L-丙交酯-co-己内酯)(PLC)、聚-L-丙交酯(PLLA)、聚-D-丙交酯(PDLA)、聚乙交酯(PGA)、聚乳酸(PLA)、聚己内酯-聚乳酸共聚物(PCL-PLA共聚物)、聚丙交酯-聚乙交酯共聚物(PLGA)、聚(三亚甲基碳酸酯)(TMC);聚己内酯(PCL)和聚(三亚甲基碳酸酯)(TMC)的共聚物;聚乳酸(PLA)、聚己内酯(PCL)和/或聚(三亚甲基碳酸酯)(TMC)的三嵌段共聚物;聚乳酸-聚环氧乙烷共聚物、聚葡萄糖酸聚羟基丁酸酯、聚酐、聚磷酸酯、聚(氨基酸)、聚二恶烷酮、纤维素、胶原、壳聚糖、其共聚物及其组合。
15.根据权利要求13所述的支架组件,其特征在于,所述载体包含选自选自以下各项的材料:聚-L-丙交酯-co-己内酯、聚丙交酯-聚乙交酯共聚物、其共聚物及其组合。
16.根据权利要求1所述的支架组件,其特征在于,所述载体的一个或多个层的厚度在约10μm至约1000μm的范围内。
17.根据权利要求1所述的支架组件,其特征在于,所述载体的一个或多个层包括热塑性弹性体或由热塑性弹性体组成。
18.根据权利要求17所述的支架组件,其特征在于,包含在所述载体的一个或多个层中的所述热塑性弹性体具有与所述支架中所包含的材料至少相同或更高的断裂伸长率。
19.根据权利要求1所述的支架组件,其特征在于,所述支架包括锥形端。
20.根据权利要求1所述的支架组件,其特征在于,所述支架为输尿管支架。
21.根据权利要求1所述的支架组件作为输尿管支架的用途。
22.用于制备根据权利要求1所述的支架组件的方法,所述方法包括:
提供支架,其中所述支架是管或螺旋线圈;
将一层或多层的载体直接设置在所述支架的外表面的至少一部分上,其中所述载体包含第一活性剂;和
将可膨胀材料和第二活性剂设置在所述一层或多层的载体的至少一部分上,以在所述一层或多层的载体的至少一部分上形成可膨胀涂层,所述可膨胀涂层适于膨胀其体积的约5倍至约160倍。
23.根据权利要求22所述的方法,其特征在于,所述提供支架包括以下至少其中一项:物理处理或化学处理支架的外表面。
24.根据权利要求23所述的方法,其特征在于,所述物理处理支架的外表面包括使支架的外表面纹理化。
25.根据权利要求24所述的方法,其特征在于,所述使支架的外表面纹理化通过蚀刻和/或用固体颗粒对所述外表面进行粗糙化而实现。
26.根据权利要求24所述的方法,其特征在于,所述化学处理支架的外表面通过等离子体处理来实现。
27.根据权利要求26所述的方法,其特征在于,所述等离子体处理包括氧等离子体处理的第一步骤和氮等离子体处理的第二步骤。
28.根据权利要求22所述的方法,其特征在于,设置所述可膨胀材料和所述第二活性剂包括:在所述一层或多层的载体的至少一部分上施加包含所述可膨胀材料和第二活性剂的液体试剂。
29.根据权利要求22所述的方法,其特征在于,设置所述可膨胀材料和第二活性剂是通过选自以下各项的方法实现的:喷涂、刷涂、浸涂、电沉积、模塑及其组合。
30.根据权利要求29所述的方法,其特征在于,所述可膨胀材料包含水凝胶或由水凝胶组成。
31.根据权利要求30所述的方法,其特征在于,设置所述可膨胀材料和第二活性剂还包括使水凝胶形成剂交联以形成水凝胶。
32.根据权利要求31所述的方法,其特征在于,所述使水凝胶形成剂交联通过使水凝胶形成剂与交联剂接触来进行。
33.根据权利要求31所述的方法,其特征在于,所述可膨胀材料还包含光引发剂。
34.根据权利要求33所述的方法,其特征在于,所述使水凝胶形成剂交联通过用电磁辐射照射所述水凝胶形成剂来实现。
35.根据权利要求34所述的方法,其特征在于,所述电磁辐射具有约365nm的波长。
36.根据权利要求34所述的方法,其特征在于,所述用电磁辐射照射所述水凝胶形成剂进行约1分钟至约15分钟的时间。
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2016
- 2016-03-15 CN CN202311555614.1A patent/CN117838375A/zh active Pending
- 2016-03-15 CN CN201680029258.1A patent/CN107920904A/zh active Pending
- 2016-03-15 WO PCT/SG2016/050119 patent/WO2016148648A1/en active Application Filing
- 2016-03-15 SG SG10201908628Q patent/SG10201908628QA/en unknown
- 2016-03-15 SG SG11201707686PA patent/SG11201707686PA/en unknown
- 2016-03-15 US US15/559,755 patent/US11357651B2/en active Active
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US11357651B2 (en) | 2022-06-14 |
SG10201908628QA (en) | 2019-11-28 |
WO2016148648A1 (en) | 2016-09-22 |
SG11201707686PA (en) | 2017-10-30 |
US20180042742A1 (en) | 2018-02-15 |
CN107920904A (zh) | 2018-04-17 |
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